Although patients with metastatic castration-resistant prostate cancer typically have limited responses to immunotherapy, a subset of patients with pretreatment evidence of active T-cell responses in their tumors experienced prolonged survival following treatment with ipilimumab in a phase II trial. These findings were published by Subudhi et al in Science Translational Medicine.
The report also provides biomarkers for identifying the subgroup of patients with metastatic castration-resistant prostate cancer who may benefit from immune checkpoint inhibition.
“Our results indicate that immune checkpoint blockade can instigate T-cell responses to tumor neoantigens, despite a low tumor mutational burden in prostate cancer,” said lead author Sumit K. Subudhi, MD, PhD, Assistant Professor of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center, in an MD Anderson press release. “We found specific markers among a subset of patients with the greatest benefit, such as T-cell density and interferon-γ signaling, that may help improve our ability to select patients for treatment with checkpoint blockade.”
“We found specific markers among a subset of patients with the greatest benefit, such as T-cell density and interferon-γ signaling, that may help improve our ability to select patients for treatment with checkpoint blockade.”— Sumit K. Subudhi, MD, PhD
Tweet this quote
Patients with the strongest responses to immune checkpoint inhibitors tend to have high levels of underlying gene mutations, which lead to production of neoantigens that can be recognized as abnormal by the immune system. Patients with prostate cancer usually have relatively low mutation levels and fewer neoantigens present. However, small groups of patients with metastatic castration-resistant prostate cancer in larger phase III trials have had favorable outcomes to checkpoint inhibitors, explained Dr. Subudhi, which drove the researchers to ask whether effective immune responses could be stimulated by checkpoint blockade in tumors with low mutation levels.
Methods and Findings
The phase II trial enrolled 30 MD Anderson patients with metastatic castration-resistant prostate cancer between January 2015 and May 2018. Of those, 29 received at least one dose of ipilimumab and were able to be included in the final analysis. Median follow-up after the first treatment was 45.5 months.
Across all patients, median progression-free survival according to radiographic imaging was 3 months (95% confidence interval [CI] = 2.5–11.2), and median overall survival was 24.3 months (95% CI = 8.5–33.9). Eight patients (28%) experienced grade 3 toxicities, the most common of which were dermatitis and diarrhea. None experienced grade 4 or 5 toxicities.
The researchers noted a “favorable” cohort of 9 patients with progression-free survival > 6 months and overall survival > 1 year, and an “unfavorable” cohort of 10 patients with progression-free survival < 6 months and overall survival < 1 year. At the time of analysis, 6 (67%) patients from the favorable cohort were alive, with survival ranging between 33 and 54 months.
By comparing pretreatment samples from these two cohorts, the researchers identified markers associated with improved responses to checkpoint blockade. Those in the favorable cohort had a higher density of cytotoxic and memory T cells in the tumor as well as increased expression of interferon (IFN)-γ signaling. Further, the researchers showed that T cells isolated from patients in the favorable cohort were capable of recognizing and responding to the neoantigens present in their tumor, whereas T cells from patients in the unfavorable group did not appear to have the same responses.
Padmanee Sharma, MD, PhD
“We were encouraged to see that prostate cancers with a low mutational burden do in fact express neoantigens that elicit T-cell responses that lead to favorable clinical outcomes,” said senior study author Padmanee Sharma, MD, PhD, Professor of Genitourinary Medical Oncology and Immunology at MD Anderson. “Our findings indicate that anti–CTLA-4 immune checkpoint therapy warrants additional studies in order to develop treatment strategies that may improve survival of patients with metastatic prostate cancer.”
Moving forward, the authors plan to investigate this question in larger, multi-institutional studies to validate the findings of the current trial.
Disclosure: The research was supported in part by the immunotherapy platform and the Prostate Cancer Moon Shot. The research also was supported by Bristol-Myers Squibb, the Stand Up To Cancer-Cancer Research Institute Immunology Dream Team Translational Research Grant, the Prostate Cancer Foundation Young Investigator Award, and the National Cancer Institute. For full disclosures of the study authors, visit stm.sciencemag.org.
